There are five broad objectives to these projects: 1) to demonstrate the specificity of the finding that the urine of patients with subacute necrotizing encephalomyelopathy (SNE, Leigh's disease) inhibits the enzyme which synthesizes thiamine triphosphate (TTP) thus leading to low proportions of TTP in the brain; 2) to seek a chemical model for SNE by the use of certain antimetabolites (pyrithiamine, plasmocid); 3) to determine whether disruption of the interchange between thiamine pyrophosphate (TPP) and TTP is the basic neurochemical deficit in both dietary thiamine deficiency and SNE; 4) to determine what is the most efficacious therapy for both conditions with respect to thiamine and its derivative thiamine tetrafurfuryldisulfide (TTFD); and 5) to determine the role of thiamine in membrane function. The specificity of our findings in SNE can be established by testing the urines of children with a wide variety of neurological disorders for inhibitory effect on TTP formation and by assaying different brain regions in patients who have died from a wide variety of neurological disorders. The relative efficacy of thiamine and TTFD in raising thiamine levels in blood, urine and cerebrospinal fluid will be compared in SNE patients. The effectiveness of therapy will be correlated with body fluid levels of thiamine. The activity of TPP-ATP phosphoryl transferase in various brain regions of rats and humans will be determined. The effect of plasmocid and pyrithiamine will be assayed with regard to 1) lesion production; 2) TPP and TTP concentrations and 3) phosphoryl transferase activity in various brain regions in rats. The protective effect of thiamine on any such effect will also be measured. The effect of plasmocid and thiamine antagonists such as pyrithiamine, 3,4 dihydroxycinnamic acid on Na24 and K42 movement in lobster walking nerves will be determined. The antagonistic action of thiamine or TTFD on any effect will be measured.